Free POST Trial Brief - District Court of Delaware - Delaware

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IN THE UNITED STATES DISTRICT COURT FOR THE DISTRICT OF DELAWARE ITEM DEVELOPMENT AB, ASTELLAS US LLC, and ASTELLAS PHARMA US, INC., Plaintiffs, v. SICOR INC. and SICOR PHARMACEUTICALS, INC., Defendants. ) ) ) ) ) ) ) ) ) ) ) )

Civil Action No.: 05-0336-SLR

PLAINTIFFS' OPENING POST TRIAL BRIEF: U.S. PATENT NO. 5,731,296
Dated: May 9, 2007 Richard K. Herrmann #405 Mary B. Matterer #2696 MORRIS JAMES LLP 500 Delaware Avenue, Suite 1500 Wilmington, DE 19801 (302) 888-6800 [email protected] Charles E. Lipsey FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, LLP Two Freedom Square 11955 Freedom Drive Reston, VA 20190-5675 (571) 203-2700 Susan H. Griffen David P. Frazier FINNEGAN, HENDERSON, FARABOW, GARRETT & DUNNER, LLP 901 New York Avenue Washington, D.C. 20001-4413 (202) 408-4000 Attorneys for Plaintiffs Astellas US LLC and Astellas Pharma US, Inc. Paul M Lukoff #96 David E. Brand #201 PRICKETT JONES & ELLIOTT, P.A. 1310 King Street Wilmington, DE 19801 (302) 888-6520 [email protected] John Scheibeler WHITE & CASE LLP 1155 Avenue of the Americas New York, NY 10036 (212) 819-8200 Attorneys for Plaintiff Item Development AB

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TABLE OF CONTENTS I. II. III. INTRODUCTION ...............................................................................................................1 STATEMENT OF THE CASE............................................................................................4 HISTORY OF ADENOSINE RESEARCH AND THE DEVELOPMENT OF THE CLAIMED INVENTION............................................................................................4 A. B. Adenosine Was Thought Too Dangerous for Human Use ......................................4 For Human Use, Research Focused on Anything But Adenosine ...........................5 1. 2. 3. C. D. Researchers Sought Adenosine Analogs .....................................................5 The Field Turned to Dipyridamole ..............................................................6 Some Researchers Investigated ATP ...........................................................6

The First Human Medical Use of Adenosine Relied on Its HeartStopping Properties..................................................................................................7 Dr. Sollevi Pioneered the Use of Adenosine Infusions in Humans .........................8 1. 2. Dr. Sollevi Pretreated Patients with Dipyridamole to Reduce the Needed Dose of Adenosine....................................................................8 Dr. Sollevi Unexpectedly Discovered that Adenosine Could Be Administered Without Dipyridamole Pretreatment and Without a Large Increase in Dose..............................................................................9

E. IV. V. VI. VII.

Leaders in the Field Were Surprised by Dr. Sollevi's Results ..............................10

THE ASSERTED CLAIMS ..............................................................................................11 SICOR'S BURDEN OF PROOF.......................................................................................12 FUKUNAGA 1982 DOES NOT ANTICIPATE THE ASSERTED CLAIMS OF THE `296 PATENT .....................................................................................................13 THE CLAIMS OF THE `296 PATENT ARE NOT INVALID FOR OBVIOUSNESS ................................................................................................................14 A. Sicor Must Prove Obviousness by Clear and Convincing Evidence Based on the Four Broad Factual Inquiries............................................................14 1. The Law of Obviousness and the Supreme Court's Decision in KSR ............................................................................................................14 i

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2.

Objective Evidence, Including Contemporaneous Statements of Skepticism by Experts in the Field and Commercial Success, Is Highly Probative of Nonobviousness ........................................................15

B.

Sicor Failed to Prove the Claimed Invention Would Have Been Obvious ..................................................................................................................17 1. Scope and Content of the Prior Art: Teaching Away ...............................17 a. b. c. d. 2. 3. 4. The History of Adenosine Research Taught Away from the Invention ..................................................................................17 The Sollevi Abstracts Taught Away from the Invention ...............19 The Fukunaga Abstracts Taught Away from the Invention ........................................................................................19 Studies of Adenosine in Normal Volunteers Taught Away from the Invention ...............................................................20

Level of Ordinary Skill in the Art..............................................................20 Differences Between the Prior Art and the Claimed Invention .................21 The Claimed Invention Would Not Have Been Obvious ..........................21 a. b. One of Ordinary Skill Would Not Have Eliminated Sollevi's Dipyridamole Pretreatment.............................................21 The ATP Infusion Reported in Fukunaga 1982 Would Not Have Led to the Use of Adenosine Infusion Without Dipyridamole Pretreatment..............................................23 Dr. Binkley's Suggested Alternative Medical Uses for Adenosine Are Untimely and Incredible .......................................26

c. 5.

Objective Evidence of Nonobviousness: Skepticism, Commercial Success, Unexpected Results, and Copying..........................28 a. The Skepticism and Ultimate Praise Expressed in the Letters By Dr. Berne and Dr. Robicsek Is Highly Probative Objective Evidence of Nonobviousness ........................28 The Commercial Success of Adenoscan Is Also Objective Evidence of Nonobviousness ........................................32

b.

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c.

The Unexpectedly Low Dose of Adenosine Required in the Absence of Dipyridamole is Further Evidence of Nonobviousness .............................................................................34 Sicor's Interest in Copying the Invention Also Demonstrates Its Nonobviousness .................................................35

d. VIII.

SICOR'S WITNESSES WERE NOT CREDIBLE AND OFFERED OPINIONS BEYOND THE SCOPE OF THEIR EXPERT REPORTS ...........................35 A. B. Dr. Binkley.............................................................................................................35 Dr. Leffler ..............................................................................................................38

IX.

CONCLUSION..................................................................................................................39

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TABLE OF AUTHORITIES FEDERAL CASES Al-Site Corp. v. VSI International, Inc., 174 F.3d 1308 (Fed. Cir. 1999)................................................................................................13 America Hoist & Derrick Co. v. Sowa & Sons, Inc., 725 F.2d 1350 (Fed. Cir. 1984)................................................................................................12 In re Bell, 991 F.2d 781 (Fed. Cir. 1993)..................................................................................................14 Burlington Industries, Inc. v. Quigg, 229 U.S.P.Q. 916 (D.D.C. 1986), aff'd, 822 F.2d 1581 (Fed. Cir. 1987) ................................16 Burlington Industries, Inc. v. Quigg, 822 F.2d 1581 (Fed. Cir. 1987) ....................................16, 29 Citizens Finance Group, Inc. v. Citizens Bank of Evans City, 383 F.3d 110 (3rd Cir. 2004) ...................................................................................................29 Coalition To Save Our Children v. State Board of Education, 90 F.3d 752 (3d Cir. 1996).......................................................................................................37 Demaco Corp. v. F. Von Langsdorff Licensing Ltd., 851 F.2d 1387 (Fed. Cir. 1988)................................................................................................33 In re Dillon, 919 F.2d 688 (Fed. Cir. 1990)..................................................................................................13 In re Dow, 837 F.2d 469 (Fed. Cir. 1988)............................................................................................16, 30 Eli Lilly & Co. v. Zenith Goldline Pharm., Inc., No. IP 99-38-C H/K, 2001 WL 1397304 (S.D. Ind. 2001) ........................................................................................34 Environmental Designs, Ltd. v. Union Oil Co. of Cal., 713 F.2d 693 (Fed. Cir. 1983)..................................................................................................16 Ferguson Beauregard/Logic Controls v. Mega System, L.L.C., 350 F.3d 1327 (Fed. Cir. 2003)................................................................................................38 In re Fielder, 471 F.2d 640 (C.C.P.A. 1973) .................................................................................................32 iv

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Forest Laboratories, Inc. v. Ivax Pharm., Inc., 438 F. Supp. 2d 479 (D. Del. 2006)...................................................................................33, 35 Gillette Co. v. S.C. Johnson & Son, Inc., 919 F.2d 720 (Fed. Cir. 1990)..................................................................................................22 Goodyear Tire & Rubber Co. v. Ray-O-Vac Co., 321 U.S. 275 (1944).................................................................................................................17 Graham v. John Deere Co., 383 U.S. 1 (1966)...............................................................................................................14, 15 Hewlett-Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464 (Fed. Cir. 1990)................................................................................................13 Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367 (Fed. Cir. 1986)..........................................................................................16, 33 Inline Connection Corp. et al. v. AOL Time Warner Inc. et al., No. 02-272-MPT (D. Del. Feb. 5, 2007) .......................................................................... 37-38 Interconnect Planning Corp. v. Feil, 774 F.2d 1132 (Fed. Cir. 1985)....................................................................................29, 31, 35 J.T. Eaton & Co. v. Atlantic Paste & Glue Co., 106 F.3d 1563 (Fed. Cir. 1997)................................................................................................17 KSR International Co. v. Teleflex, Inc., No. 04-1350 (Apr. 30, 2007) ...............................................................................................3, 15 Life Techs., Inc. v. Clontech Laboratories, Inc., 224 F.3d 1320 (Fed. Cir. 2000)................................................................................................20 Lindemann Maschinenfabrik GmbH v. America Hoist & Derrick Co., 730 F.2d 1452 (Fed. Cir. 1984)..........................................................................................16, 34 Ortho-McNeil Pharm., Inc. v. Mylan Laboratories, Inc., 348 F. Supp. 2d 713 (N.D. W. Va. 2004) ....................................................................33, 34, 35 Power Integrations, Inc. v. Fairchild Semiconductor International, Inc., No. 04-1371-JJF (D. Del. Sept. 20, 2006) ...............................................................................37 Pro-Mold & Tool Co. v. Great Lakes Plastics, Inc., 75 F.3d 1568 (Fed. Cir. 1996)............................................................................................16, 17

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Procter & Gamble Co. v. Paragon Trade Brands Inc., 989 F. Supp. 547 (D. Del. 1997)..............................................................................................35 Ruiz v. A.B. Chance Co., 234 F.3d 654 (Fed. Cir. 2000)................................................................................15, 16, 17, 33 Schumer v. Laboratories Computer System, Inc., 308 F.3d 1304 (Fed. Cir. 2002)................................................................................................12 Standard Oil Co. v. America Cyanamid Co., 774 F.2d 448 (Fed. Cir. 1985)..................................................................................................20 Stratoflex, Inc. v. Aeroquip Corp., 713 F.2d 1530 (Fed. Cir. 1983)................................................................................................28 Structural Rubber Products Co. v. Park Rubber Co., 749 F.2d 707 (Fed. Cir. 1984)..................................................................................................13 TP Laboratories, Inc. v. Prof'l Positioners, Inc., 724 F.2d 965 (Fed. Cir. 1984)..................................................................................................12 Tec Air, Inc. v. Denso Manufacturing Michigan, Inc., 192 F.3d 1353 (Fed. Cir. 1999)..........................................................................................17, 32 Threadgill v. Armstrong World Industrial, Inc., 928 F.2d 1366 (3d Cir. 1991)...................................................................................................32 U.S. v. Adams, 383 U.S. 39 (1966).......................................................................................................16, 28, 30 Ultra-Tex Surfaces, Inc. v. Hill Brothers Chemical Co., 204 F.3d 1360 (Fed. Cir. 2000)................................................................................................12 Union Oil Co. of Cal. v. Atlantic Richfield Co., 208 F.3d 989 (Fed. Cir. 2000)..................................................................................................13 Uniroyal, Inc. v. Rudkin-Wiley Corp., 837 F.2d 1044 (Fed. Cir. 1988)..........................................................................................14, 28 United States v. Stelmokas, 100 F.3d 302 (3d Cir. 1996).....................................................................................................32 W.L. Gore & Associate, Inc. v. Garlock, Inc., 721 F.2d 1540 (Fed. Cir. 1983)................................................................................................28

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FEDERAL STATUTES 35 U.S.C. § 103..............................................................................................................................14 35 U.S.C. § 282........................................................................................................................12, 38 Fed. R. Civ. P. 26(a)(2)(B) ............................................................................................................37 Fed. R. Civ. P. 37(c)(1)..................................................................................................................37 Fed. R. Evid. 803(3).................................................................................................................29, 32 Fed. R. Evid. 901(b)(8) ..................................................................................................................32

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I.

INTRODUCTION The patent in suit, U.S. Patent No. 5,731,296 (the `296 patent), concerns the discovery by

Dr. Alf Sollevi in the mid-1980s that "adenosine" could be safely administered to human patients by continuous infusion to preferentially dilate arteries. Such adenosine infusions are used extensively today in the diagnosis of coronary artery disease in patients unable to perform a standard exercise stress test. Driven by a desire to enter this lucrative market, the Defendants contend here that the claimed methods would have been obvious. Their contentions, however, ignore the long history of the dangerous side effects of adenosine that foreclosed or limited its use in humans. Aided by hindsight, it is improperly contended that the steps taken in the prior art to avoid or ameliorate these dangerous effects were obviously unnecessary. The contention is belied by the evidence of what people actually working in this field at the relevant time did and said before and after the invention was made known to them. Despite its widespread use today, for nearly 50 years after it was first discovered and tested, adenosine was considered too toxic and too short-acting to be of any use whatsoever as a human pharmaceutical. Early studies showed that adenosine could interrupt transmission of the electrical signals in the heart, slowing the heart rate or even stopping the heart from beating. The rapid metabolism of adenosine into "uric acid" raised concerns about kidney damage. By the early 1980s, the only known medical use for adenosine was based not on its vasodilating properties but on its negative effects on the beating heart. Administering a tiny amount of adenosine solution, in a single, short-acting bolus (i.e., rapid injection) was shown to terminate a particular form of heart arrhythmia. In the face of this long negative history associated with adenosine, Dr. Alf Sollevi, a young researcher in Sweden, undertook to administer adenosine to humans, not as a short-acting bolus, but in a continuous intravenous infusion lasting close to an hour. He did so in order to

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achieve "controlled hypotension," i.e., to drop blood pressure significantly, during brain surgery. He did not, however, administer adenosine alone. Concerned about adenosine's effect on the heart and its capacity to form the toxic uric acid metabolite, he pretreated his patients with "dipyridamole" to reduce the necessary dose of adenosine. Indeed, the prior art suggested that dipyridamole pretreatment could reduce the amount of adenosine needed by 10 to as much as 200-fold. With dipyridamole pretreatment, Dr. Sollevi found that the needed blood pressure reductions could be achieved with an average adenosine dose of 140 mcg/kg/min. Infusing adenosine without dipyridamole pretreatment was unthinkable, as the much higher doses thought to be required (1,400 mcg/kg/min or more) would surely have led to serious side effects. Dr. Sollevi proceeded against the conventional wisdom to conduct experiments to see if controlled hypotension could be achieved with adenosine alone. He discovered, surprisingly, that large doses of adenosine were not required in the absence of dipyridamole pretreatment. Instead, a dose increase of only about 50% was sufficient to cause the same amount of vasodilation without dipyridamole. The ability to infuse adenosine safely without dipyridamole pretreatment allowed adenosine to be used in a variety of medical techniques where the rapid termination of adenosine's effects was desirable. On the basis of his unexpected discovery, Dr. Sollevi filed the patent application that led to the `296 patent. It is thus seen that the only known human medical uses for adenosine took precautions to protect the patient from the known negative side effects of adenosine. Either the dose was limited to a small, short-acting bolus or dipyridamole was employed to lower doses used for infusion. The Defendants now contend that safety concerns did not exist and that it would have

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been obvious to use adenosine in humans without either of these safeguards. The contemporaneous evidence is to the contrary. In addition to the prior art scientific publications that taught away from the invention, the Court has actual letters written to Dr. Sollevi by leaders in the field praising his invention and expressing surprise that he had not encountered safety problems. While the Court questioned at trial whether such unpublished correspondence is appropriately considered, courts, including the Supreme Court, have recognized that correspondence written at the time of the invention, long before any possible litigation-driven bias, is highly probative of nonobviousness, as discussed in detail in § VII.B.5.a., infra. Plaintiffs also offered testimony from Dr. Richard Klabunde and Dr. Sollevi, who were both active in the field at the relevant time and performing adenosine research. The Defendants here have offered no such contemporaneous evidence. They rely instead on the opinions of Dr. Phillip Binkley, who had no experience with adenosine in the early 1980s. Working with the benefit of hindsight, Dr. Binkley asserted that the myriad safety concerns described in the prior art and in the writings of the experts of the day would not have dissuaded an ordinary physician. Tellingly, Dr. Binkley's opinions frequently strayed well beyond the bounds of his expert report, and were, in fact, contrary to his prior deposition testimony. Since the trial in this matter, the Supreme Court has made its first pronouncement in decades on the law of obviousness. KSR Int'l Co. v. Teleflex, Inc., No. 04-1350 (Apr. 30, 2007). The Court there reaffirmed the bedrock principle guiding resolution of this case -- that an inventor proceeding contrary to conventional wisdom and achieving something unexpected is the hallmark of nonobviousness. Id. at 12.1

The evidence and the legal authority compelling judgment in favor of Plaintiffs in this case, summarized herein, is compiled, organized, and annotated in Plaintiffs Proposed Findings (continued...) 3

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II.

STATEMENT OF THE CASE Patent owner Item Development AB (Item) and licensees Astellas US LLC and Astellas

Pharma US, Inc. (collectively Astellas) brought this patent infringement suit under the Hatch-Waxman Act after Defendants Sicor Inc. and Sicor Pharmaceuticals, Inc. (collectively Sicor) prepared and filed an abbreviated new drug application (ANDA) seeking approval to market a generic version of Astellas's branded pharmaceutical Adenoscan®.2 (TX-4; TX-7.) Adenoscan is an adenosine solution for continuous infusion used to dilate coronary arteries during cardiac diagnostic procedures. Sales of Adenoscan in 2005 exceeded $300 million. (TX-19; White 1235:4-10.) Having conceded infringement just before trial, Sicor challenges the validity of claims 1, 3, 7, and 9 of the `296 patent. (D.I. 129, ¶ 2.) The case was tried to the Court beginning on February 12, 2007. III. HISTORY OF ADENOSINE RESEARCH AND THE DEVELOPMENT OF THE CLAIMED INVENTION A. Adenosine Was Thought Too Dangerous for Human Use

Adenosine was first administered to animals and humans in the 1920s and 30s. (See TX-35; TX-187; Klabunde 516:4-22.) These studies showed adenosine to be a potent vasodilator, but also a powerful inhibitor of the electrical signals that cause the heart to beat. (See TX-35 at 236; TX-187 at 258; Klabunde 516:4-22.) As described in the contemporary literature of the 1980s, adenosine's ability to stop the heartbeat discouraged researchers for decades from any consideration of adenosine as a human pharmaceutical agent:

(...continued) of Fact and Conclusions of Law filed concurrently herewith. Reference herein to the more detailed discussions of the evidence and applicable law in that document is to "PFF ___" and "PCL ___," respectively. 2 Adenoscan® (hereinafter Adenoscan) is a registered trademark of Astellas. 4

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Adenosine was first administered to human subjects in 1930 and 1933 to treat cardiac arrhythmias. The development of serious side effects with large boluses of the drug (temporary cardiac arrest) led the authors to conclude that adenosine was not "a useful therapeutic preparation for the treatment of heart disease," a view which discouraged further research. (TX-48 at 2229; Klabunde 520:23-522:2; see also TX-36 at 1254; Klabunde 517:2-17.) B. For Human Use, Research Focused on Anything But Adenosine 1. Researchers Sought Adenosine Analogs

Having rejected adenosine itself as a potential human drug, many investigators tried to develop adenosine analogs that would have the desirable effects of adenosine without its undesirable adverse side effects. (Binkley 326:18-328:1; Strauss 769:8-770:20.)3 As stated in a typical publication from the early 1970s: The use of adenosine in cardiovascular therapy has been precluded both by the transitory nature of its vasodilator effects and by its toxic actions on the heart. It would seem feasible however that certain analogs of adenosine may be found which have the coronary vasodilatory activity of adenosine, but which have greater duration of action in vivo and which lack the cardiac depressant action of the parent compound. (TX-214 at 415 (emphasis added); Binkley 326:23-328:1; Strauss 770:16-20.) One example of such efforts to find useful adenosine analogs involved efforts to use "ethyl-adenosine" to dilate coronary arteries in connection with cardiac imaging techniques. (See, e.g., TX-1184; Binkley 328:2-329:5.) Unlike adenosine, ethyl-adenosine did not slow the heartbeat or cause hypotension in dog studies. (See TX-176 at 419; TX-1184 at 406; Strauss Plaintiffs elicited a portion of the factual testimony of Sicor's expert Dr. Strauss to be admitted in both this case and the related action, CV No. 05-337 SLR. Defendants objected to admission of Dr. Strauss's testimony here, urging that he was proffered solely as an expert in the parallel action. Dr. Strauss's testimony is appropriate here because he is not being offered to provide expert opinions, but merely to recount his understanding of facts and circumstances in the field of adenosine research in the late 1970s. Plaintiffs identified Dr. Strauss as a fact witness in this case in lists exchanged with Sicor months before trial, in November 2006. 5
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772:3-772:17.) Moreover, it had a longer lasting effect when administered as a bolus. (See TX-1184 at 406; Strauss 771:6-772:2.) Based on positive animal studies, it was viewed as a potential pharmaceutical agent for diagnosing coronary artery disease in humans. (See TX-232 at 248; Strauss 767:19-768:9, 771:15-773:13, 774:19-776:4.) But tests in actual human patients showed that the drug caused dangerous side effects, including inadequate blood flow in the heart (termed "ischemia") and chest pain. (TX-259 at 472; Strauss 773:14-21.) Thus, further work with ethyl-adenosine ceased. (See Strauss 775:17-776:4.) 2. The Field Turned to Dipyridamole

Following the failure of ethyl-adenosine, researchers continued to search for a vasodilator for use in human cardiac imaging. Notably, they did not turn to adenosine. Instead they chose dipyridamole. (See TX-93; Binkley 329:6-330:6.) Despite the fact that dipyridamole was believed to act, at least in part, by raising endogenous adenosine levels (TX-93 at 758; Binkley 330:8-25), nobody even suggested that adenosine itself should be used instead. (Strauss 774:13-18.) 3. Some Researchers Investigated ATP

A 1982 abstract by Dr. Fukunaga reported on the intravenous administration of a continuous infusion of adenosine triphosphate ("ATP") to cause hypotension in surgical patients. (TX-42 (hereinafter "Fukunaga 1982"); Binkley 161:23-162:13.) The abstract described ATP as a "physiological intracellular substance, which relaxes and dilates vascular smooth muscles, including coronary and cerebral arteries." (TX-42; Klabunde 508:8-24.) ATP is not adenosine. It is a high energy molecule with a different chemical structure. (Klabunde 505:17-506:18.) ATP was known in the early 1980s to have different properties and to act through different receptors than adenosine. (See TX-151; Klabunde 506:11-18; 6

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510:8-513:24.) Indeed, a study by Moir and Downs in the 1970s demonstrated that ATP was significantly more potent than adenosine as a coronary vasodilator. (TX-199 at 1386; Klabunde 551:3-552:10.) ATP was also known to break down into a variety of metabolites which rapidly interconverted with one another. (See TX-126 at 612; Binkley 272:16-274:9; DTX-2008.) Adenosine was one of the metabolites of ATP, which was ultimately converted to uric acid. Because accumulation of uric acid had the potential to cause kidney damage in patients, Dr. Fukunaga recommended in a second abstract in 1984 that patients be pretreated with dipyridamole prior to ATP infusion, which greatly reduced the necessary dose of ATP to be administered by a factor of 12 or more. (See TX-51; Klabunde 540:10-541:23.) C. The First Human Medical Use of Adenosine Relied on Its HeartStopping Properties

The first human medical use of adenosine was proposed in 1983 by Dr. Berne and his colleagues at the University of Virginia. Dr. Berne was then one of the world's leading authorities on adenosine. (Binkley 317:19-318:19.) The proposed medical use -- termination of an arrhythmia known as "PSVT" with a rapid, short-acting "bolus" injection of adenosine -- employed the known heart-stopping properties of adenosine (termed "AV block") to obtain a positive effect in this unique patient population. (TX-36; TX-45; Klabunde 522:3-523:23; Binkley 325:14-18.) Those effects, however, were obviously undesirable for any other use. (Klabunde 523:24-524:25.) Even for this application, there were concerns about serious side effects because "[o]verdosage might lead to prolonged asystole [cardiac arrest], hypotension or other tachyarrhythmias." (TX-45 at 423.)

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D.

Dr. Sollevi Pioneered the Use of Adenosine Infusions in Humans 1. Dr. Sollevi Pretreated Patients with Dipyridamole to Reduce the Needed Dose of Adenosine

Dr. Sollevi pioneered the first administration of adenosine as an intravenous infusion in humans. Dr. Sollevi's interest and insight into adenosine had grown out of work he began as a medical student. (Sollevi 429:2-12.) He spent nearly six years studying adenosine's effects in animals before attempting to administer it to humans for controlled hypotension in patients undergoing neurosurgery for cerebral aneurysms. (Sollevi 434:12-435:4.) A cerebral aneurysm is a "bulb" or bubble on a blood vessel in the brain that could rupture, causing bleeding and death. (Sollevi 435:5-23.) In the 1980s, neurosurgeons sought to drastically reduce the patient's blood pressure (roughly 40%) during aneurysm surgery, causing "slack" in the "bubble" to avoid rupture. (Sollevi 435:24-436:24.) Dr. Sollevi was concerned about adenosine's effects on the heartbeat, its potential to cause ischemia (especially in patients with heart disease), and its potential to cause toxic levels of the metabolite, uric acid, which could damage a patients' kidneys. (Sollevi 438:8-15.) So in addition to carefully monitoring the electrocardiograms and testing metabolite levels, he pretreated his patients with dipyridamole to inhibit the metabolism of adenosine and allow a much lower adenosine dose to be used. (Sollevi 438:17-439:6.) He excluded from his studies, patients with a history of heart disease because he feared adenosine would cause ischemia in such patients. (Sollevi 441:16-442:2.) Dr. Sollevi published the results of his initial studies in abstracts in 1983 and 1984. (TX-1170 (hereinafter "Sollevi I"); TX-37 (hereinafter "Sollevi II").) These abstracts demonstrated that, in the presence of a dipyridamole pretreatment, an average dose of 140 mcg/kg/min of adenosine, infused intravenously, would reduce mean blood pressure by about 40 8

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percent. (TX-1170; TX-37; Binkley 258:2-5, 258:10-13.) The abstracts did not mention the possibility of eliminating the dose-reducing dipyridamole pretreatment or provide any guidance about whether one could determine a safe and effective dose that would induce hypotension in the absence of that pretreatment. 2. Dr. Sollevi Unexpectedly Discovered that Adenosine Could Be Administered Without Dipyridamole Pretreatment and Without a Large Increase in Dose

A variety of studies in the prior art in the mid-1980s suggested that much higher amounts of adenosine would have to be infused in patients if the dipyridamole pretreatment were eliminated. Plaintiffs' expert, Dr. Klabunde, published an article in 1983 demonstrating that the short (<10 seconds) half-life of adenosine could be dramatically lengthened by "the usual therapeutic concentrations of dipyridamole." (TX-101 at 25; Klabunde 503:21-504:2.) A study by Kassell and colleagues in dogs showed that dipyridamole pretreatment had reduced the required dose of adenosine by nearly 200-fold. (TX-40 at 73; Klabunde 534:9-536:1.) Moreover, Dr. Fukunaga's 1984 abstract concerning administration of ATP in the presence of dipyridamole showed a large increase, from 12-fold to as much as 50-fold more, in the dose of ATP required without dipyridamole. (TX-51; Klabunde 1050:24-1051:8.) Notably, a later study by Biaggioni in April 1985 showed that administration of adenosine by intravenous infusion without dipyridamole pretreatment at doses up to 140 mcg/kg/min in 5 conscious normal volunteers did not cause hypotension, further supporting the perception that higher doses would be needed without dipyridamole. (TX-1187; Klabunde 555:3-556:14.) Despite the many studies suggesting it would be futile, Dr. Sollevi proceeded in the winter of 1983 to 1984 to perform studies in human patients intravenously infusing adenosine without an initial dipyridamole pretreatment. (Sollevi 446:1-14, 447:13-449:18.) He explained 9

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that his prior work with dipyridamole pretreatment had not answered his concerns about AV block, accumulation of uric acid, or possible ischemia because those same effects could well be observed at the higher doses required in the absence of dipyridamole pretreatment. (Sollevi 447:13-448:8.) Dr. Sollevi's perspective was that he had "no information" on the amount of adenosine that would be required apart from his own animal studies suggesting that as much as 20-fold higher doses would be needed. (Sollevi 448:2-449:8.) To his surprise, Dr. Sollevi found that only a small increase of approximately 50 percent in the adenosine dose was required in the absence of dipyridamole. (Sollevi 450:5-451:6.) The mean dose only increased from about 140 mcg/kg/min with dipyridamole to approximately 214 mcg/kg/min without the pretreatment. (TX-1169 at 232; Sollevi 450:5-451:3.) Moreover, the increased dose did not significantly raise the level of uric acid accumulated during the hypotension period. (TX-1169 at 232, Table 4; Sollevi 451:7-21.) Finally, elimination of the dipyridamole pretreatment allowed the controlled hypotension to be rapidly terminated when no longer needed during surgery. (Sollevi 448:11-16.) E. Leaders in the Field Were Surprised by Dr. Sollevi's Results

Leaders in adenosine research were surprised by Dr. Sollevi's results with adenosine infusion. Dr. Sollevi recounted at trial how the dean of the field, Dr. Berne, could not believe that adenosine could be administered safely by infusion, referring to Dr. Sollevi at their first meeting as the "crazy Swede." (Sollevi 452:25-454:3; Klabunde 1052:4-1053:4.) In subsequent correspondence between the two scientists, Dr. Berne reiterated his surprise, stating "[o]ne thing I don't understand is how you avoid atrioventricular heart block [AV block] with doses of adenosine that are required to greatly lower arterial pressure." (TX-49.) Dr. Sollevi's insight had led him to do what the recognized leader in the field had considered impossible. 10

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Still another adenosine researcher, Dr. Francis Robicsek, was also surprised by and skeptical about the safety of Dr. Sollevi's methods. Dr. Robicsek was head of a major thoracic surgery center and had done his own research on adenosine infusion in dogs in the early 1980s. (TX-255; Klabunde 1053:5-1055:1.) Upon reading one of Dr. Sollevi's articles about infusing adenosine in patients, he wrote to the chief editor of the journal asking whether Dr. Sollevi had taken adequate steps to ensure that the kidneys would not be damaged by adenosine infusion due to the buildup of the toxic metabolite, uric acid. (TX-410; Sollevi 464:13-468:7.) This was a concern that Dr. Sollevi himself had shared but overcome and that Dr. Fukunaga had addressed by recommending dipyridamole pretreatment. (TX-51; Klabunde 540:15-541:8; Sollevi 447:13-448:1, 449:14-18.) The journal editor found that Dr. Robicsek's concerns warranted a reply from Dr. Sollevi and asked Dr. Sollevi to respond. (TX-293; Sollevi 465:8-466:24.) The subsequent correspondence between the researchers revealed that Dr. Robicsek himself had considered administering adenosine infusions to humans, but had not proceeded in view of his concerns over uric acid. (TX-265; Sollevi 471:13-472:17.) Dr. Robicsek further graciously congratulated Dr. Sollevi for succeeding where he had failed. (TX-265; Sollevi 471:13-472:17.) The story of the `296 patent reflects Dr. Sollevi's courage and insight that led him to do what others had feared to do. IV. THE ASSERTED CLAIMS Dr. Sollevi filed a patent application relating to his work with adenosine infusion on September 24, 1985. (TX-308; Sollevi 431:5-25.) That application ultimately led to the `296 patent-in-suit, which issued on March 24, 1998. As discussed above, the asserted claims of the patent relate to Dr. Sollevi's conclusion that patients administered an adenosine infusion without pretreatment with dipyridamole exhibit clear selective arterial vasodilation without significant 11

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venous dilation, allowing adenosine to be used for medical purposes, such as controlled hypotension, and the other uses set forth in the original patent specification. (See TX-308; Sollevi 433:23-434:11.) The asserted claims are claims 1, 3, 7, and 9 of the `296 patent. For purposes of illustration, claim 3 reads: 3. A method of selectively vasodilating the arteries of a human patient without inducing significant venous dilation and without pretreatment with dipyridamole, comprising continuously administering into the blood stream of said patient by intravenous administration about 0.05 milligrams to about 0.30 milligrams [about 50 micrograms to about 300 micrograms] of adenosine per kilogram body weight per minute. (TX-275 at col. 22, ll. 20-26.) V. SICOR'S BURDEN OF PROOF As the party challenging the validity of the `296 patent, Sicor bears the burden of proof, and it must carry that burden by clear and convincing evidence. 35 U.S.C. § 282; Schumer v. Lab. Computer Sys., Inc., 308 F.3d 1304, 1315 (Fed. Cir. 2002). The challenger's burden "is constant and remains throughout the suit" and "does not shift at any time to the patent owner." TP Labs., Inc. v. Prof'l Positioners, Inc., 724 F.2d 965, 971 (Fed. Cir. 1984). Patents are presumed valid, and each claim within a patent is independently presumed valid, even if other claims within the patent are held invalid. 35 U.S.C. § 282. If a patent challenger alleges invalidity based on prior art the PTO considered during prosecution of the patent, that challenger has the "added burden of overcoming the deference that is due to a qualified government agency presumed to have properly done its job." Ultra-Tex Surfaces, Inc. v. Hill Bros. Chem. Co., 204 F.3d 1360, 1367 (Fed. Cir. 2000) (quoting Am. Hoist & Derrick Co. v. Sowa & Sons, Inc., 725 F.2d 1350, 1359 (Fed. Cir. 1984). In other words, "the 12

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challenger's `burden is especially difficult when the prior art was before the PTO examiner during prosecution of the application.'" Al-Site Corp. v. VSI Int'l, Inc., 174 F.3d 1308, 1323 (Fed. Cir. 1999) (quoting Hewlett-Packard Co. v. Bausch & Lomb Inc., 909 F.2d 1464, 1467 (Fed. Cir. 1990)). Sicor's three primary references in this matter, Fukunaga 1982, Sollevi I, and Sollevi II, were all before the patent office and are listed on the face of the `296 patent. (TX-275.) Consequently, Sicor bears the "especially difficult" burden of proving invalidity based on art that was considered during patent prosecution. VI. FUKUNAGA 1982 DOES NOT ANTICIPATE THE ASSERTED CLAIMS OF THE `296 PATENT Sicor has not come close to carrying its burden of proving anticipation of claims 1, 3, 7, or 9 of the `296 patent by Fukunaga 1982. A party seeking to invalidate a patent under § 102 for anticipation must show that the allegedly invalidating prior art contains each and every element of the claimed invention. Union Oil Co. of Cal. v. Atl. Richfield Co., 208 F.3d 989, 994-95 (Fed. Cir. 2000); In re Dillon, 919 F.2d 688, 715 (Fed. Cir. 1990). If even one element is not shown in the reference, then it does not anticipate. See Structural Rubber Prods. Co. v. Park Rubber Co., 749 F.2d 707, 716 (Fed. Cir. 1984). Each of claims 1, 7, and 9 recites "administering into the blood stream of said patient adenosine" at various concentrations. (TX-275 at col. 22 (emphasis added).) Claim 3 contains a similar recitation, further limiting the method of adenosine administration to "intravenous administration." (TX-275 at col. 22.) Dr. Binkley repeatedly acknowledged that the Fukunaga 1982 abstract described administration of ATP, not adenosine. (Binkley 164:18-165:4; 169:18-21; 190:9-12; 243:14-22.) These admissions should end the inquiry. ATP is not adenosine, and the claims require administering adenosine. (Klabunde 505:7-506:6.) Even Dr. 13

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Binkley, despite offering his opinion at trial that the asserted claims were anticipated in view of Fukunaga 1982, admitted that at his deposition he had said he was not asserting anticipation. (Binkley 243:23-244:1.) Other deficiencies in Sicor's anticipation argument are set forth at PFF § IV. VII. THE CLAIMS OF THE `296 PATENT ARE NOT INVALID FOR OBVIOUSNESS A. Sicor Must Prove Obviousness by Clear and Convincing Evidence Based on the Four Broad Factual Inquiries

To succeed in proving obviousness, Sicor must prove by clear and convincing evidence that "the differences between the subject matter sought to be patented and the prior art are such that the subject matter as a whole would have been obvious at the time the invention was made to a person having ordinary skill in the art to which said subject matter pertains." See 35 U.S.C. § 103. 1. The Law of Obviousness and the Supreme Court's Decision in KSR

Obviousness under 35 U.S.C. § 103 is a conclusion of law based on the factual inquiries set forth in Graham v. John Deere Co., 383 U.S. 1, 17-18 (1966), which include consideration of (1) the scope and content of the prior art, (2) the differences between the prior art and the claimed subject matter as a whole, (3) the level of skill in the art, and (4) objective evidence of nonobviousness. Additional factual findings include determining what the prior art teaches and whether it "teaches away" from the claimed invention. In re Bell, 991 F.2d 781, 784 (Fed. Cir. 1993). These findings must be made viewing the invention in the context of the state of the art that existed at the time it was made. Uniroyal, Inc. v. Rudkin-Wiley Corp., 837 F.2d 1044, 105051 (Fed. Cir. 1988).

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In its first obviousness case in many years, the Supreme Court has now clarified the standard for obviousness in the context of a simple mechanical "combination" invention. KSR Int'l Co., slip op. at 12. The Court held that "[t]he combination of familiar elements according to known methods is likely to be obvious when it does no more than yield predictable results." Id. By contrast, the Court noted, "when the prior art teaches away from combining certain known elements, discovery of a successful means of combining them is more likely to be nonobvious." Id. Furthermore, prior art warnings about risks involved in the claimed invention and obtaining unexpected results also support a conclusion of nonobviousness. Id. KSR confirmed that fact finders must avoid "the distortion caused by hindsight bias and must be cautious of arguments reliant upon ex post reasoning." Id. at 17 (citing Graham, 383 U.S. at 36). In this regard, the Court acknowledged that "it can be important to identify a reason that would have prompted a person of ordinary skill in the relevant field to combine the elements in the way the claimed new invention does." Id. Moreover, while prior art combinations resulting in "predictable solutions" leading to "anticipated success" are indicators of obviousness, combinations that "work together in an unexpected and fruitful manner" are not obvious. See id. at 12. 2. Objective Evidence, Including Contemporaneous Statements of Skepticism by Experts in the Field and Commercial Success, Is Highly Probative of Nonobviousness

The assessment of obviousness also requires examination of objective evidence of nonobviousness. Graham, 383 U.S. at 17-18. The Federal Circuit has emphasized the need for evaluating objective evidence of nonobviousness. Ruiz v. A.B. Chance Co., 234 F.3d 654, 667 (Fed. Cir. 2000) (stating that "secondary considerations when present, must be considered in determining obviousness") This evaluation must be made during a court's consideration of 15

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whether the claimed invention is obvious, not after such a determination is complete. Lindemann Maschinenfabrik GmbH v. Am. Hoist & Derrick Co., 730 F.2d 1452, 1461 (Fed. Cir. 1984). "It is the secondary considerations that are often most probative and determinative of the ultimate conclusion of obviousness or nonobviousness." Pro-Mold & Tool Co. v. Great Lakes Plastics, Inc., 75 F.3d 1568, 1573 (Fed. Cir. 1996). Such secondary considerations include the extent of the commercial success of the patented invention, unexpected results compared to the prior art, skepticism in the field, and any copying of the invention by others. Id. at 1574 (finding issues of material fact raised by evidence of copying and commercial success); see, e.g., Hybritech, Inc. v. Monoclonal Antibodies, Inc., 802 F.2d 1367, 1382 (Fed. Cir. 1986) (crediting evidence of commercial success, unexpected results, and skepticism). Evidence of initial skepticism, surprise, or incomprehension upon learning of the invention and thereafter praising its value is strong evidence of nonobviousness. U.S. v. Adams, 383 U.S. 39, 52 (1966); Envtl. Designs, Ltd. v. Union Oil Co. of Cal., 713 F.2d 693, 697-98 (Fed. Cir. 1983); Ruiz, 234 F.3d at 668 ("Proceeding contrary to the accepted wisdom . . . is strong evidence of unobviousness.") (internal citations omitted). This is particularly true where "the skepticism is expressed at the time of the invention, in a nonadversarial setting." Burlington Indus., Inc. v. Quigg, 229 U.S.P.Q. 916, 919 (D.D.C. 1986), aff'd, 822 F.2d 1581 (Fed. Cir. 1987). Such evidence of skepticism need not be derived from the technical literature but may include personal communications and comments by experts in the field. See, e.g., Adams, 383 U.S. 39 (crediting contemporaneous doubts expressed in correspondence by scientists and government experts who observed initial demonstrations of claimed battery); Burlington Indus., Inc., 822 F.2d at 1584 (crediting inventor's testimony that mill operators dismissed him as "crazy" upon first learning of his invention); In re Dow, 837 F.2d 469, 472-73 (Fed. Cir. 1988) 16

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(crediting evidence of skepticism expressed by expert chemist in a report sent to company management around time the invention was made). Commercial success of an invention is also evidence that the invention would not have been obvious. Goodyear Tire & Rubber Co. v. Ray-O-Vac Co., 321 U.S. 275, 279 (1944); ProMold, 75 F.3d at 1573-74. Commercial success is usually shown by significant sales in a relevant market. J.T. Eaton & Co. v. Atl. Paste & Glue Co., 106 F.3d 1563, 1571 (Fed. Cir. 1997). Additional evidence that is probative of commercial success includes growth in market share, increases in sales, and replacing earlier units sold by others. Tec Air, Inc. v. Denso Mfg. Michigan, Inc., 192 F.3d 1353, 1360-1361 (Fed. Cir. 1999); Ruiz, 234 F.3d at 668. B. Sicor Failed to Prove the Claimed Invention Would Have Been Obvious 1. Scope and Content of the Prior Art: Teaching Away a. The History of Adenosine Research Taught Away from the Invention

The prior art here taught away from Dr. Sollevi's invention, which was directly contrary to the conventional wisdom of the day. The medical literature dating back to the 1920s showed that adenosine was long believed inappropriate for use as a vasodilator in human patients. (See, e.g., TX-48 at 2229.) Reasons for this belief included adenosine's ability to slow or stop the beating of the heart by inhibiting electrical conduction in the AV node (AV block), as well as its short half-life, which, historically, was viewed as a liability rather than a benefit. (See, e.g., TX-214 at 415.) This general understanding in the art was summed up in the publication by Maguire, which stated, "The use of adenosine in cardiovascular therapy has been precluded both by the transitory nature of its vasodilator effects and by its toxic actions on the heart." (Id.) An additional problem associated with adenosine was its ability to be metabolized into uric acid, a

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compound capable of crystallizing in the kidneys, causing them to shutdown. (See TX-51; TX-112; TX-255 at 19; TX-441 at 158; Sollevi 440:18-441:15, 461:10-464:12.) These concerns about the safety and short acting nature of adenosine led to use in the prior art of anything but adenosine alone. Instead, researchers tried to use adenosine analogs, (like ethyl-adenosine) or drugs that act indirectly, like dipyridamole, instead of adenosine. See § III.B., supra. For more than 50 years after its discovery, there was no attempt to use exogenously administered adenosine for any medical use in human patients. (Strauss 767:8-18.) In 1983, Dr. Berne described the first human medical use of adenosine as a treatment for the heart arrhythmia, PSVT, but this use emphasized adenosine's negative effects on cardiac conduction and involved individual rapid bolus doses, not longer-lasting infusions. (See TX-36; Klabunde 522:3-524:20.) More to the point, these studies effectively demonstrated in the clinic what those in the art had always feared, that exogenously administered adenosine would interrupt the beating of the heart. For treatment of PSVT, this was a useful and brief effect, controlled through short bolus (i.e., rapid injections) administration. (Klabunde 523:24-524:8.) For any other use, the effect would have been highly undesirable, and if it persisted as long as adenosine was administered, would render adenosine infusion impossible. (See Klabunde 524:4-20.) Consequently the use of adenosine for treatment of PSVT would have strongly discouraged, not encouraged, the use of adenosine infusions for vasodilation. Indeed, this bias was so firmly entrenched in the field that cardiologists initially resisted using Astellas's Adenoscan brand adenosine as a pharmacologic stress agent for fear of inducing AV block even in the 1990s. (Klose 1516:3-1517:1.)

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b.

The Sollevi Abstracts Taught Away from the Invention

It was against this backdrop that Dr. Sollevi published the Sollevi I and Sollevi II abstracts, in 1983 and early 1984, respectively. (TX-37; TX-1170; Sollevi 442:3-443:11.) Sicor urges that these abstracts demonstrated the safety of adenosine infusion in man and provided the necessary reason for one of ordinary skill in the art to carry out the methods claimed in the `296 patent. (See Binkley 136:23-137:8, 154:1-155:12.) But every patient described in the abstracts received dipyridamole pretreatment as a safety precaution for the stated purpose of minimizing the required dose of adenosine. (TX-1170; TX-37; Klabunde 527:12-20.) The abstracts themselves did not suggest or imply administering adenosine without dipyridamole pretreatment.4 To the contrary, the prior art taught away from removing this precautionary step by showing adenosine to be capable of serious adverse effects, particularly at higher doses. (Klabunde 529:6-530:8, 537:20-538:6, 558:5-19.) To be sure, it was technically possible to attempt adenosine infusion without dipyridamole pretreatment, but the prior art would have discouraged one of skill in the art from doing so. c. The Fukunaga Abstracts Taught Away from the Invention

Sicor also cited the Fukunaga 1982 abstract, suggesting that its disclosure of ATP administration without dipyridamole pretreatment would have led a person of ordinary skill to administer adenosine while eliminating the dipyridamole pretreatment described in Sollevi I and Sollevi II. (See, e.g., Binkley 192:2-23.) But that assertion is directly contrary to Fukunaga's own recommendation, published as prior art just two years later in the Fukunaga 1984 abstract,
4

Sicor's reliance on the conclusory statements in each abstract referring to the ability of adenosine to induce hypotension is misplaced. The context of these statements is clearly within a methodology that used dipyridamole as a safety measure to reduce the required dose of adenosine, thereby avoiding its known risks. (Klabunde 529:6-530:8; 530:18-532:3.) 19

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which urged the use of ATP rather than adenosine for controlled hypotension and further recommended use of dipyridamole pretreatment to dramatically lower the dose and prevent side effects, particularly uric acid build up, from high doses of ATP. (TX-51; Klabunde 540:15541:8.) d. Studies of Adenosine in Normal Volunteers Taught Away from the Invention

The Biaggioni abstract (TX-1187) relied upon by Sicor proposed no human medical use for adenosine infusions without dipyridamole pretreatment, nor did it assess the effect of such adenosine infusions in human patients. (Klabunde 552:21-23, 556:10-14.) The results that were reported, indicating that a 140 mcg/kg/min dose of adenosine without dipyridamole pretreatment did not reduce blood pressure in 5 normal volunteers, would have reinforced the view that much higher adenosine doses would have been required to achieve controlled hypotension without dipyridamole pretreatment. (Klabunde 555:3-556:2.) 2. Level of Ordinary Skill in the Art

Both sides agree that a person of ordinary skill in the art with which the `296 patent is concerned would be a cardiologist with training in internal medicine and a cardiology fellowship. (Klabunde 515:11-25.) Consistent with the requirement that a person of ordinary skill be considered "presumed to think along conventional lines," such a physician would have been acutely aware of the adverse cardiac side effects that had been associated with adenosine for decades and unlikely to discount them without significant reassurance. See Life Techs., Inc. v. Clontech Labs., Inc., 224 F.3d 1320, 1325 (Fed. Cir. 2000) (citing Standard Oil Co. v. Am. Cyanamid Co., 774 F.2d 448, 454 (Fed. Cir. 1985)).

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3.

Differences Between the Prior Art and the Claimed Invention

Unlike the methods set forth in claims 1, 3, 7, and 9 of the `296 patent, the Sollevi I and Sollevi II abstracts describe administering an intravenous infusion of adenosine at a mean dose of approximately 140 mcg/kg/min in conjunction with dipyridamole pretreatment. (See TX-37; TX-1170.) The presence of a dipyridamole pretreatment is the essential difference between the prior art publications and the claimed methods. (Klabunde 527:2-20.) To prove its case, Sicor must prove by clear and convincing evidence, and without the use of hindsight, that it would have been obvious for one of ordinary skill to perform the claimed methods, which lack a dipyridamole pretreatment and are limited to dose ranges of 10 to 150 mcg/kg/min (claim 7); 50 to 300 mcg/kg/min (claim 3); and less than 350 mcg/kg/min (claims 1 and 9). This it has not done. In particular, Sicor has not proven that one of ordinary skill would then have had any legitimate reason to eliminate the dipyridamole treatment and administer an adenosine infusion in the claimed dose range to achieve controlled hypotension -- the sole use disclosed for adenosine infusions in the prior art -- or to believe that such a method could be successfully practiced. Sicor relies entirely on the opinions of Dr. Binkley, which are deeply contaminated with impermissible hindsight. 4. The Claimed Invention Would Not Have Been Obvious a. One of Ordinary Skill Would Not Have Eliminated Sollevi's Dipyridamole Pretreatment

The prior art references relied on by Dr. Binkley suggested only one medical use for adenosine infusion: controlled hypotension. (Binkley 285:11-20; Klabunde 528:12-529:1; DTX-2002.) The prior art included a dipyridamole pretreatment for the specific purpose of lowering the needed adenosine dose in view of the known negative effects of adenosine. (See TX-1170; Klabunde 527:12-20.) To achieve controlled hypotension required administering 21

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sufficient adenosine, in the presence of dipyridamole, to reduce blood pressure by approximately 40%. (Binkley 284:5-285:20.) The Sollevi Abstracts report that an adenosine dose of 140 mcg/kg/min was required on average under these conditions. Acknowledging that one of ordinary skill would not have expected that controlled hypotension could be achieved at an adenosine dose of only 140 mcg/kg/min in the absence of dipyridamole, Dr. Binkley opined that one of ordinary skill would have eliminated the dipyridamole pretreatment and then gradually increased the adenosine dose to study whether vasodilation sufficient to induce controlled hypotension would occur. (Binkley 342:17-343:6; 345:8-346:18.) That assertion, which acknowledges the lack of any reasonable expectation of success, is nothing more than an invitation to experiment and falls well short of proving obviousness. See Gillette Co. v. S.C. Johnson & Son, Inc., 919 F.2d 720 (Fed. Cir. 1990) (explaining a general disclosure that invites experimentation without a reasonable expectation of success does not render invention obvious). Indeed, the record is clear that concerns about the side effects associated with larger doses of adenosine would have discouraged an ordinary cardiologist from eliminating the dipyridamole pretreatment in the first place. (Klabunde 529:6-530:8.) The prior art suggested that the dose of adenosine would need to be drastically increased, from 10 to as much as 200-fold higher, in the absence of dipyridamole. (See, e.g., Klabunde 535:13-536:8, 557:10-558:19.) Even with dipyridamole, Sollevi I and II indicated that 140 mcg/kg/min was required on average for controlled hypotension. Those two facts would have made eliminating the dipyridamole pretreatment out of the question, for they suggested the need for a huge adenosine dose of 1,400 mcg/kg/min or more. (Klabunde 537:20-538:6.) Moreover, the expectation that much higher doses would be required in the absence of dipyridamole would not have reasonably suggested the 22

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usefulness of doses within the claimed dose ranges. Thus, rather than encouraging one of ordinary skill to eliminate the dipyridamole pretreatment, the prior art would have strongly discouraged it. b. The ATP Infusion Reported in Fukunaga 1982 Would Not Have Led to the Use of Adenosine Infusion Without Dipyridamole Pretreatment

Sicor suggests that one of ordinary skill would have concluded that the hypotension reported in the Fukunaga 1982 abstract following administration of ATP was, in fact, due solely to conversion to adenosine and would have concluded, therefore, that adenosine itself could be safely administered for surgical hypotension at the claimed dose range without a dipyridamole pretreatment. Such a conclusion would not have come from the abstract itself, which stated only that "ATP is a physiological intracellular substance, which relaxes and dilates vascular smooth muscles including coronary and cerebral arteries." (TX-42; Klabunde 508:8-24.) Moreover, by the time the `296 patent was filed in 1985, it had been well established through the work of Dr. Geoffrey Burnstock that ATP had its own receptors (designated P2) as compared to adenosine (whose receptor had been designated P1). (TX-151; Klabunde 513:20-24.) Dr. Binkley opined that one of ordinary skill would have known that administering ATP at the dose range described in Fukunaga 1982 (200-600 mcg/kg/min) would correspond to an "equivalent" dose of 97 to 290 mcg/kg/min, taking into account the relative molecular weights of the different compounds. (Binkley 167:5-168:7, 170:18-171:2.) In other words, he opined that on a weight basis, one microgram of adenosine would be equivalent to about two micrograms of ATP. (See Binkley 259:11-260:20.) Dr. Binkley's opinion, however, was based on the "simplifying assumption" (which was in fact merely speculation (Binkley 271:18-272:14)), that 100% of the administered ATP in Fukunaga 1982 would have been rapidly converted to 23

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adenosine and that it was the adenosine not the ATP that was causing the hypotensive effect. (Binkley 167:12-168:7.) This conjecture cannot satisfy Sicor's burden of proof. For example, Dr. Binkley's simplifying assumption does not take into account (1) that ATP is metabolized into various metabolites that would interconvert with one another (and even reform ATP), (2) that administration of exogenous ATP can cause cells to release their own endogenous ATP into the bloodstream, or (3) that adenosine would not simply "pool' in the body, but would further break down into other metabolites. (Binkley 272:15-274:9; DTX-2008; cf. Klabunde 507:8-508:3.) Indeed, despite characterizing adenosine as the "end product" of ATP metabolism, Dr. Binkley admitted that adenosine itself would have been further degraded to uric acid. (Binkley 168:8-25, 274:1-9.) Consequently, it would have been impossible to predict or calculate the amount of adenosine formed in the bloodstream of a patient infused with ATP. (Klabunde 507:8-508:3.) Moreover, the human data contradicted Dr. Binkley's assumption that two micrograms of ATP would be equivalent to one microgram of adenosine. The Fukunaga 1984 abstract reported that, on average, 32 micrograms of ATP lowered blood pressure by about 40% in patients pretreated with dipyridamole. (TX-51; Klabunde 550:4-14; Binkley 257:12-15; DTX-2002.) Under Dr. Binkley's assumption, a corresponding dose of 16 micrograms of adenosine should have had a similar effect. (Binkley 258:25-260:1; Klabunde 549:4-550:14.) In actual fact, Dr. Sollevi needed 140 micrograms of adenosine, nearly 10 times as much as Dr. Binkley's assumption predicted, to achieve a similar blood pressure reduction after dipyridamole pretreatment. (Binkley 260:2-20; Klabunde 550:15-24.) Thus, comparing the dose of adenosine required to induce hypotension following dipyridamole pretreatment with the corresponding dose of ATP would have shown that ATP was 24

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a much more potent vasodilator in humans than adenosine, a result that would have utterly contradicted the notion that the effects of ATP were simply due to its metabolism into adenosine. (Klabunde 550:20-25, 1044:5-25.) In this regard, one of ordinary skill would have understood that if ATP were working indirectly through breakdown into adenosine, then ATP would be less potent than adenosine, which it was not. (See TX-152 at 198; Binkley 1459:20-1460:14; see also Klabunde 1212:13-1213:8.) Instead, the evidence clearly pointed to a direct action by ATP, even if that action was mixed with action by other vasodilating metabolites, including adenosine. (See, e.g., Klabunde 1044:5-25.) Most telling is what Dr. Fukunaga actually did in the early 1980s. Sicor suggests that one of ordinary skill in the art presented with the Fukunaga 1982 abstract showing ATP-induced hypo